Abstract A major question in melanoma biology with clinical relevance is why red-haired individuals are at a high risk of developing melanoma. Variants in the melanocortin-1-receptor (MC1R) gene, encoding a trimeric G protein-coupled receptor activated by ?-melanocyte-stimulating hormone (?-MSH), are frequently associated with red or blonde hair, fair skin, freckling and skin sensitivity to ultraviolet (UV) light, and several red hair color variants (RHC-variants) of MC1R also associate with increased melanoma risk. However, not all of these associations have been attributed to phenotype, suggesting that some variants affect melanoma risk independent of phenotype. Using an in vivo model system, we reported that some MC1R RHC-variants synergize with UV to induce melanoma independently of their effects on pigmentation. Understanding precisely how MC1R RHC-variants differentially affect melanoma biology is therefore a key issue to connect red-heads and melanoma susceptibility. Recently, we further reported a novel modification of MC1R protein, palmitoylation, which is crucial in the activation of MC1R signaling. We also found a new critical role of ?-MSH/MC1R in centromere integrity. Herein, we will further investigate the regulators and mechanisms underlying MC1R protein palmitoylation and its role in protecting centromere integrity, which could help identify new potential strategies for therapeutic intervention of melanoma. In addition, we will use newly generated MC1R conditional RHC-variant mouse models to dissect the tumor suppressive functions of MC1R in melanoma initiation in vivo, specify its role in protecting centromere integrity and determine the role of MC1R protein palmitoylation in UV-induced melanoma development. Given the connection among MC1R variants, red hair/fair skin phenotype and melanoma development, these studies will help answer a question with clinical relevance ?why red-haired individuals are so prone to developing melanoma? and will lead to the identification of novel preventive and therapeutic strategies for melanoma, especially melanomas in red-heads.